Preparation of 2-alkyl-3-(4,5-dihydroisoxazol-3-yl) halobenzenes

ABSTRACT

A novel process for preparing the compounds of the formula I                    
     where: 
     n is 0, 1 or 2; 
     R 1 , R 2  are C 1 -C 6 -alkyl; 
     R 3 , R 4 , R 5  are hydrogen or C 1 -C 6 -alkyl, or R 4  and R 5  together form a bond; 
     R 6  is Cl, Br, 
     which comprises a synthesis sequence starting from 1,2-dialkylbenzenes of the formula II                    
     with subsequent halogenation to give 3,6-dihalo-1,2-dialkylbenzenes, haloalkylation to give benzyl bromides, oxidation to give benzaldehydes, oximation, reaction with alkenes to give isoxazoles, conversion into thioethers and, if appropriate, oxidation to give sulfenyl or sulfonyl derivatives of the formula I.

This application is a divisional application of application Ser. No.10/141,236, filed on May 9, 2002 now U.S. Pat. No. 6,603,017, which isin turn a divisional of application Ser. No. 09/856,037 Filed on May 17,2001, now U.S. Pat. No. 6,548,677 which is a 371 of PCT/EP99/08844 filedNon 17, 1999.

The present invention provides a process for preparing2-alkyl-3-(4,5-dihydroisoxazol-3-yl)halobenzenes.

2-Alkyl-3-(4,5-dihydroisoxazol-3-yl)halobenzenes are starting materialsfor preparing 2-alkyl-3-(4,5-dihydroisoxazol-3-yl)acylbenzenes which canbe used in the field of crop protection. Such compounds are described asherbicidally active compounds in WO 98/31681, for example.

It is an object of the present invention to provide an improvedpreparation process for 3-heterocyclyl-substituted benzoyl derivativesas described, for example, in WO 98/31681. The preparation processdescribed in WO 98/31681 for the2-alkyl-3-(4,5-dihydroisoxazol-3-yl)acylbenzenes and their precursors(2-alkyl-3-(4,5-dihydroisoxazol-3-yl)bromobenzenes) is not ideal for thelarge-scale industrial preparation of these compounds, since thesynthesis involves a plurality of steps and the yield of the respectiveend product is relatively low, based on the starting materials employedin the first step of the synthesis.

We have found that this object is achieved by the process according tothe invention, which permits the preparation of the3-heterocyclyl-substituted benzoyl derivatives or their variousprecursors in good yield and on an advantageous economical scale. Theprocess according to the invention has the advantage that the totalyield of the end products in question, based on the starting materialsused, is higher than the yield in the processes described in WO98/31681. Furthermore, the starting materials can be prepared in asimple manner or can be purchased even in relatively large amounts, by anumber of independent suppliers of raw materials, so that overall, acheaper, economical and safe process for the large-scale industrialreparation of herbicidally active compounds is provided.

The present invention provides a process for preparing the compounds ofthe formula I

where:

n is 0, 1 or 2;

R¹, R² are C₁-C₆-alkyl;

R³, R⁴, R⁵ are hydrogen or C₁-C₆-alkyl, in particular methyl, or R⁴ andR⁵ together form a bond;

R⁶ is Cl, Bra,

which comprises one or more of the following process steps a)-g):

a) halogenation of a 1,2-dialkylbenzene of the formula II

in which the radicals R¹ can be identical or different and are asdefined above with halogens, in particular chlorine or bromine, to givethe 3,6-dihalo-1,2-dialkylbenzenes of the formula III

b) reaction of a 3,6-dihalo-1,2-dialkylbenzene of the formula III withhydrogen peroxide and a halogenating agent, preferably HBr, to give thebenzyl halides, in particular the benzyl bromides, of the formula IV

in which the radicals R¹ and R⁶ are as defined above;

c) oxidation of the benzyl bromides of the formula IV with an oxidizingagent to give the aldehydes of the formula V

in which the substituents R¹ and R⁶ are as defined above;

d) reaction of the compounds of the formula V with hydroxylamine andbase to give the corresponding oximes of the formula VI

in which the substituents R¹ and R⁶ are as defined above;

e) reaction of the oximes of the formula VI with an alkene of theformula VII

in which R³ to R⁵ are as defined in claim 1, in the presence of ahypochlorite, to give the 4,5-dihydroisoxazole of the formula VIII

in which R¹ and R³ to R⁶ are as defined in claim 1;

f) reaction of the compound of the formula VIII with metal thiolates ofthe formula IX

R²—S⁻ M⁺  IX

in the presence of a solvent to give the thioethers of the formula X

in which R¹ to R⁶ are as defined in claim 1;

g) if appropriate reaction of the thioethers of the formula X with anoxidizing agent to give the corresponding alkylsulfonyl or alkylsulfenylderivatives of the formula I where n is the number 1 or 2.

In all cases, C₁-C₆-alkyl is a straight-chain or branched alkyl grouphaving 1-6 carbons, such as, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, n-pentyl or n-hexyl. This appliesanalogously to the C₁-C₆-alkoxy group.

R⁴ and R⁵ together may also represent a bond, resulting in thecorresponding isoxazole derivatives. In this case, R³ is preferablyhydrogen.

The reaction sequence leading to the compounds of the formula I iscompiled in the synoptical scheme below:

Hereinbelow, the individual steps are briefly illustrated in moredetail.

1. Step a)

The halogenation is carried out by methods known from the literature,preferably using chlorine gas. Suitable solvents are alcohols, such as,for example, ethanol.

2. Step b)

The reaction is carried out under the following conditions: solvent:solvents which are inert to the bromination, such as: benzene,tert-butylbenzene, tert-amylbenzene, halogenated hydrocarbons, such asmethylene chloride, chloroform, chlorobenzene 1,2-dichloroethane, carbontetrachloride, dichlorobenzene or trichlorobenzene. Mixtures of thesesolvents may also be used. Brominating agent: bromine, bromine salts orHBr, preferably in an aqueous solution. Particular preference is givento using technical-grade azeotropic mixtures of HBr.

3. Step c)

NMMO: N-methylmorpholine N-oxide

Suitable for the oxidation are, for example, oxidizing agents, such asperacids, peroxides, hypochlorite, chlorine, sodium bromate andpotassium peroxodisulfate; hydrogen peroxide is particularly suitable.It is known from the literature (DE-29 48 058) that alkyl halides andbenzyl halides can be oxidized to the corresponding carbonyl compoundsusing amine oxides of tertiary amines or pyridine. The reaction iscarried out under the following conditions: amine oxides: amine oxideshaving aliphatic, cycloaliphatic and aromatic radicals, such astrimethylamine, dimethylcyclopentylamine, dimethylamine. Furthermoreamine oxides having cycloaliphatic radicals which are interrupted byheteroatoms (O; N). N-alkyl- and N-aryl-substituted piperidines,piperazines and morpholines.

Alternatively, it is possible to apply the method described in U.S. Pat.No. 2,902,515, where allyl halides are reacted with alkali metalnitronates to give the corresponding aldehydes. The conditions are, forexample, the following: solvent:—alcohols, such as methanol, ethanol,isopropanol, ethers, such as dioxane, THF, dipolar aprotic solvents,such as, for example, N,N-dialkylformamides, -acetamides,N-methylpyrrolidone, dimethylpropylene urea; tetramethyl urea, DMF, NMP,acetonitrile. Preference is given to methanol. The nitronates aregenerated as follows: reaction of lower nitroalkanes with alkali metalhydroxides (aqueous NaOH or KOH) or reaction of lower nitroalkanes withalkali metal alkoxides, such as KOtBu in butanol or sodium methoxide inmethanol. The resulting nitronates are reacted with the benzyl halides.The reaction is carried out at temperatures from −10° C. to 80° C.,preferably from 0° C. to 50° C. This is followed by aqueous work-up.

4. Step d)

The benzaldoxime can be obtained in virtually quantitative yield bystandard processes starting from the corresponding aldehydes, byreaction with hydroxylamine in the presence of acid.

5. Step e)

The reaction of the benzaldoxime of the formula VI with alkenes of theformula VII to give compounds of the formula VIII proceeds via differentintermediates. Since the first reaction step comprises the formation ofan intermediate hydroxamic acid halide, a suitable oxidizing agent and asource of halogen or even the halogen itself have to be present. Thesecond reaction step is the elimination of hydrogen halide giving thenitrile oxide, which reaction requires basic conditions. The final,third step is the cycloaddition of the nitrile oxide to the alkene.

This sequence can be carried out stepwise by customary processes using,for example, the free halogens bromine or chlorine for forming thehydroxamic acid halide. Since the hydroxamic acid halides have atendency to decompose, they have to be converted quickly, using a base,into the even more sensitive nitrile oxides, which in most cases aretrapped in situ with the alkene.

In the process according to the invention, these individual steps havenow been combined advantageously in a “one-pot reaction”. To this end,the reaction is generally carried out in a solvent such as, for example,a halogenated alkane, such as dichloroethane or methylene chloride, oran aromatic, such as benzene, toluene, chlorobenzene, nitrobenzene orxylene, which dissolves the organic component but does not interferewith the reaction. An aqueous alkali metal hypohalite solution,preferably 1-2 equivalents of commercially available sodium hypochloritesolution, is added as halogenating agent and simultaneously as base, andthe alkene is added in parallel or immediately afterwards. Thus, thereaction mixture is usually biphasic, since the organic solvent and thealkali metal hypohalite solution mix only incompletely. To complete theconversion, it may be advantageous to add 3-50% of sodium acetate orpotassium acetate; however, this is not essential.

Gaseous alkenes of the formula VII are introduced, liquid alkenes aremetered in correspondingly. The alkenes are generally employed in amolar ratio of from 1 to 5:1, based on the oxime VI.

The reaction is carried out at 0-80° C., preferably 20-50° C. Thereaction is carried out under a pressure of 0-20 bar, preferably 0-6bar.

6. Step f)

The reaction of alkali metal thioalkylates or copper thioalkylates witharomatic halogen compounds affords aromatic alkyl thioethers.

The reaction is carried out under the following conditions: solvent:alcohols, such as methanol, ethanol, propanol, tert-butanol, water,ethers, such as dioxane, THF, polar aprotic solvents, for exampleN,N-dialkylformamides, -acetamides, N-methylpyrrolidone,dimethylpropyleneurea; tetramethylurea, acetonitrile, propionitrile,dimethyl sulfoxide; preferably: methanol, DMF, NMP. Temperature: 0° C.to 170° C., preferably 30° C. to 120° C., particularly preferably 40° C.to 100° C.

Practice: The alkali metal thioalkylate, for example sodiumthiomethylate, can be employed as a solid or as an aqueous or methanolicsolution or be prepared and employed in situ from the alkyl mercaptan,for example methyl mercaptan, and an alkali metal alkoxide or hydroxideor alkaline earth metal alkoxide or hydroxide base, for example sodiummethoxide, potassium ethoxide, sodium hydroxide or potassium hydroxide.The reaction can also be carried out under reduced pressure, byadditionally adding a high-boiling dipolar aprotic solvent, withdistillative removal of the low-boiling solvent, for example water ormethanol. By adding copper powder (0.01-10 mol %) as catalyst, it isfrequently possible to achieve a complete and faster reaction. Thethioalkylation is generally carried out at 0-100° C., preferably at20-80° C.

7. Step g)

The oxidation is carried out similarly to the reaction of the chlorinederivative (R¹═Cl), described in: WO 98/31681 (cf. p. 8 line 32 to p.11, line 25).

The invention is illustrated in more detail in the embodiments below.

EXAMPLE 1

Preparation of 3,6-dichloro-1,2-xylene

The chlorination of 1,2-xylene is carried out by methods known from theliterature, using chlorine gas. The solvent used for xylene is ethanol.

EXAMPLE 2

Preparation of 3,6-dichloro-2-methylbenzyl bromide

170.1 g (0.97 mol) of 3,6-dichloro-1,2-xylene are initially charged in1180 ml of chlorobenzene, and 4.9 g of conc. H₂SO₄ and 203.1 g (1.18mol) of 47% strength hydrobromic acid are added. The mixture is heatedto 70° C., and 0.9 g of AIBN are added. Over a period of 5 h, 353.7 g(1.04 mol) of a 10% strength solution of hydrogen peroxide are added at70-75° C., the mixture is stirred at 70-75° C. for 30 min, washed twicewith 400 ml of water and once with 400 ml of saturated sodiumbicarbonate solution, and the chlorobenzene is then distilled off.

This gives 242.9 g of a product which is 78.4% pure (9.5% of startingmaterial, 10.4% of dibromo compound). Yield: 77.2%. GC/MS: m/z: 252.

EXAMPLE 3

Preparation of 3,6-dibromo-2-methylbenzyl bromide

183.2 g (0.65 mol) of 3,6-dibromo-1,2-xylene are initially charged in750 ml of chlorobenzene, and 2 g of conc. H₂SO₄ and 270.7 g (1.57 mol)of 47% strength hydrobromic acid are then added. The reaction mixture isheated to 70° C. and 0.3 g of AIBN are added. Over 14 h, 237.7 g (0.7mol) of a 10% strength solution of hydrogen peroxide are added at 75-77°C., the mixture is stirred for another 120 min., washed 2× with 250 mlof water and once with 250 ml of saturated sodium bicarbonate solution,and the chlorobenzene is then distilled off.

This gives 219.3 g of a product which is 72.3% pure (15.3% of startingmaterial, 6.4% of dibromo compound). Yield: 70.9%. GC/MS: m/z: 340.

EXAMPLE 4

Preparation of 3,6-dichloro-2-methylbenzaldehyde

122.4 g (0.68 mol) of a 30% strength solution of sodium methoxide aredissolved in 1030 ml of methanol, and 56.4 g ( 0.57 mol) of 90% pure2-nitropropane and 188.5 g (0.52 mol) of 61.6% pure3,6-dichloro-2-methylbenzyl bromide are then added. The reaction isexothermic to 53° C., and the mixture is then stirred for 90 min. Thereaction mixture is poured into 2.5 l of water, the pH is adjusted to pH7.0 using 10% strength HCl, the mixture is extracted three times with 1l of ethyl acetate, and the organic phases are combined, washed twicewith 500 ml of saturated NaCl solution, dried over Na₂SO₄ andconcentrated under reduced pressure: the 161.0 g of crude product aredistilled using a 10 cm column packed with 10 mm Raschig rings. Thecrystals from the last fractions are filtered. This gives 9.8 gcomprising 85.9% of the desired product and 4.5% and 6.9% of isomers.Yield: 9.7%. The residue is distilled over a Spaltrohr column, givinganother 3.2 g of 94.3% pure product.

EXAMPLE 5

Preparation of 3,6-dichloro-2-methylbenzaldehyde

67.4 g (0.19 mol) of 72.2% pure 3,6-dichloro-2-methylbenzyl bromide isinitially charged in 280 ml of acetonitrile. At 0-5° C., a solution of54.0 g (0.46 mol) of N-methylmorpholine N-oxide and 280 ml ofacetonitrile is added over a period of 25 min, and the mixture isstirred at 0-8° C. for 1 h. The precipitate is filtered off with suctionand taken up in 280 ml of acetonitrile, and 250 g (0.42 mol) of 20%strength NMO in acetonitrile are then added at 40° C. The reactionmixture is stirred at 40° C. for 1 h and concentrated under reducedpressure, the residue is taken up in 250 ml of methylene chloride andthe mixture is washed three times with 250 ml of water, dried overNa₂SO₄ and concentrated under reduced pressure. This gives 32.9 g of aproduct which is 92.6% pure.

Yield: 84.2%. ¹H-NMR (CDCl₃): 2.6 ppm (s, 3H, Me), 7.2 ppm (d, 1H,arom-H), 7.45 ppm (d, 1H, arom-H), 10.5 ppm (s, 1H, CHO).

EXAMPLE 6

Preparation of 3,6-dichloro-2-methylbenzaldoxime

198 g (0.975 mol) of 93% pure 3,6-dichloro-2-methylbenzaldehyde and416.2 g (0.634 mol) of a 25% strength aqueous solution of hydroxylaminesulfate are mixed in 1.5 l of toluene and heated at 80° C. Over a periodof 2 h, 109.2 g (1.36 mol) of 50% strength NaOH are then added dropwisesuch that the pH is between 3 and 5. Stirring at 80° C. is continued for1 h, and the phases are then separated at 80° C. The organic phase iswashed once with 250 ml of water. The organic phase is concentrated andthe residue is recrystallized from cyclohexane. This gives 165.4 g ofthe aldoxime (83.3% of theory). ¹H-NMR: (DMSO-D₆): 2.4 ppm (s, 3H, Me),7.4 ppm (d, 1H, arom-H), 7.5 ppm (d, 1H, arom-H), 8.3 ppm (s, 1H, NH),11.7 ppm (s, 1H, OH).

EXAMPLE 7

Preparation of 3,6-dibromo-2-methylbenzaldoxime

10 g (0.42 mol) of 3,6-dibromo-2-methylbenzaldehyde and 178.5 g (0.272mol) of a 25% strength aqueous solution of hydroxylamine sulfate aremixed in 1.2 l of toluene and heated at 80° C. Over a period of 2 h,109.2 g (1.36 mol) of 50% strength NaOH are then added dropwise suchthat the pH is between 3 and 5. Stirring at 80° C. is continued for 1 h,the mixture is stirred at room temperature overnight and the phases arethen separated at 80° C. The organic phase is washed once with 350 ml ofwater. The organic phase is concentrated and the residue isrecrystallized from cyclohexane. This gives 113.9 g (93% of theory) ofthe aldoxime.

¹H-NMR: (DMSO-D₆): 2.45 ppm (s, 3H, Me), 7.5 ppm (d, 1H, arom-H), 7.6ppm (d, 1H, arom-H), 8.1 ppm (s, 1H, NH), 11.65 ppm (s, 1H, OH).

EXAMPLE 8

Preparation of 3-(3,6-dichloro-2-methylphenyl)-4,5-dihydroisoxazole

In a pressure container, 50 g (0.25 mol) of3,6-dichloro-2-methylbenzaldoxime are dissolved in 750 ml of methylenechloride. 16 g of ethylene are applied, and 620 g of a 12.5% strengthsolution of NaOCl are then pumped in at room temperature, and themixture is stirred overnight. The pressure vessel is vented, and theorganic phase is then separated off, washed once with water and dried,and the solvent is removed under reduced pressure. This gives 58 g ofproduct (95% pure) (95% of theory). ¹H-NMR (DMSO-D₆): 2.3 ppm (s, 3H,Me), 3.3 ppm (t, 2H, CH2), 4.5 ppm (t, 2H, CH2), 7.45 ppm (d, 1H,arom-H), 7.6 ppm (d, 1H, arom-H).

EXAMPLE 9

Preparation of 3-(3,6-dibromo-2-methylphenyl)-4,5-dihydroisoxazole

68 g (0.23 mol) of 3,6-dibromo-2-methylbenzaldoxime are dissolved in 750ml of methylene chloride in a pressure container. 20 g of ethylene areapplied, and 620 g of a 12.5% strength solution of NaOCl are then pumpedin at room temperature, and the mixture is stirred overnight. Thepressure vessel is vented, and the organic phase is then separated off,washed once with 250 ml of water and dried, and the solvent is removedunder reduced pressure. This gives 77 g of product (95% pure) (99% oftheory).

EXAMPLE 10

Preparation of3-(3-chloro-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole

20 g (0.083 mol) of 3-(3,6-dichloro-2-methylphenyl)-4,5-dihydroisoxazoleare dissolved in 120 ml of NMP. At 0° C., 6.7 g (0.09 mol) of sodiumthiomethoxide are added over a period of 40 min, and the mixture is thenstirred overnight. The reaction mixture is stirred into 360 ml of waterand extracted four times with 70 ml of toluene, the combined organicphases are washed once with 70 ml of water and the organic phase isconcentrated. The residue (an isomer mixture) is distilled at 150-170°C. under a reduced pressure of 1 mbar. The main fraction is purifiedchromatographically. This gives 4.5 g of a product which is 83% pure(17% of theory).

EXAMPLE 11

Preparation of3-(3-bromo-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole

25 g (0.075 mol) of 3-(3,6-dibromo-2-methylphenyl)-4,5-dihydroisoxazoleare initially charged in 12 mol of NMP. At a temperature of 100° C. andat a reduced pressure of 100 mbar, 29.3 g (0.09 mol) of a 21.5% strengthmethanolic solution of sodium thiomethoxide are added dropwise over aperiod of 40 min. The reaction mixture is stirred at 100° C. for 3 h andthen stirred into 250 ml of water and extracted three times with 100 mlof toluene. The combined organic phases are washed once with 100 ml ofwater and then concentrated under reduced pressure. This gives 17.5 g ofa dark oil. GC/MS shows, in addition to other isomers, 52.3% of thedesired product. MSm/z: 287.

EXAMPLE 12

Preparation of3-(3-chloro-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole

1.4 g (6.2 mmol) of3-(3-chloro-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole aredissolved in 3 ml of glacial acetic acid, and 30.7 mg of sodiumtungstate dihydrate are added. At 25-40° C., 2.1 g (18.6 mmol) ofhydrogen peroxide are added dropwise, and the reaction mixture isstirred for 3 h. The reaction mixture is then poured into 1.5 ml ofwater, the mixture is cooled to 0° C. and the resulting precipitate isfiltered off with suction, washed five times with 10 ml of water anddried under reduced pressure. This gives 1.23 g of product.

We claim:
 1. A process for preparing a thioether of the formula X

which comprises the steps of e) reacting an oxime of the formula VI

with an alkene of the formula VII

in the presence of a hypochlorite, to give the 4,5-dihydroisoxazol ofthe formula VIII

and f) reacting compounds of the formula VIII with a metal thiolate ofthe formula IX R⁷—S⁻M⁺  IX in the presence of a solvent to give thethioether of the formula X, wherein, in the above formulae, R¹, R² areC₁-C₆-alkyl; R³, R⁴, R⁵ are hydrogen or C₁-C₆-alkyl, or R⁴ and R⁵together form a bond; R⁶ is Cl or Br.
 2. The process of claim 1 whichincludes the step of preparing the oxime of the formula VI by reactingan aldehyde of the formula V

with hydroxylamine and base to give the corresponding oxime of formulaVI.